Although retrospective studies suggest that a lifelong pattern of high mental activity is protective against Alzheimer's Disease (AD), prospective longitudinal studies have not been done. As well, the contribution of social and/or physical activity to AD risk-reduction has not been adequately evaluated in controlled clinical studies nor has the potential benefit of long-term, intensive cognitive rehabilitation in AD patients. The availability of AD transgenic mice make it possible to investigate these issues in fully-controlled longitudinal studies. Our preliminary studies indicate that "complete" environmental enrichment (e.g., cognitive, social, and physical activity) is both protective and therapeutic against cognitive impairment in AD transgenic mice ? this, without affecting brain beta-amyloid deposition. The present project will first elucidate the role of each contributing component (e.g., cognitive,social, and physical) to the protective ability of complete environmental enrichment; this isolation of enrichment's contributing components is impossible to achieve in clinical studies. Second, this project will evaluate the potential of both continous and session-restricted environmental enrichment as a treatment to cognitively-impaired AD transgenic mice. All cognitive rehabilitative therapeutic in AD patients are session-restricted, so it is important to investigate this protocol in AD transgenic models. Third, a variety of brain neuropathologic and neurochemical processes will be assessed that could be mechanistically involved in the cognitive benefits provided by environmental enrichment or it's various component activities. These processes include neurogenesis, neurodegeneration, oxidative stress, neuroinflammation, and growth factor modulation. Collectively, the studies of this project are of substantial public health significance because they investigate the potential for "modifiable" factors (cognitive, social, physical activity) to protective against or treat AD, as well as provide important insight into likely cellular/molecular mechanisms that may be involved therein.